Intercellular communication in the central nervous system requires the precise control of the duration and the intensity of neurotransmitter action at specific molecular targets. Plasma membrane neurotransmitter transporters are responsible for the high-affinity uptake of neurotransmitters by neurons and glial cells at the level of their plasma membrane.
Parkinson's disease (PD) is a neurodegenerative disorder that is characterized, in part, by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It affects 1.5% of the global population over 65 years of age. The lack of dopamine causes the classical motor symptoms of bradykinesia, rigidity and resting tremors. These symptoms are improved by current dopamine replacement strategies, which include levodopa (1-DOPA, the precursor of dopamine) and dopamine receptor agonists, as well as monoamine oxidase B (MAOB) inhibitors and catechol O-methyltransferase inhibitors.
Current therapeutic development in PD includes approaches such as re-formulations (for example, extended release formulation) of existing drugs that are approved for PD, re-positioning of compounds that are approved for other indications (such as the antihypertensive drug isradipine, the antiepileptic topiramate or methylphenidate) and development of novel small-molecule and gene therapy-based approaches. The therapeutic development pipelines appear to be vigorous on the surface. However, once dopaminergic compounds are removed from the development pipeline, the current landscape is far less encouraging. Such dopaminergic therapies include new formulations of existing drugs, which are more likely to provide incremental rather than profound improvements over existing therapies.
Many of the therapies that are currently under development—including both dopaminergic and non-dopaminergic compounds—are focused on improvement of motor control, fluctuations and dyskinesias. Far fewer approaches address the other two key unmet clinical needs, specifically: alleviating non-motor symptoms; and disease modification and/or neuroprotection.
Neurodegenerative disorders are a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have much different aetiology. Many are hereditary; some are secondary to toxic or metabolic processes. Free radicals are highly reactive molecules or chemical species capable of independent existence. Generation of highly Reactive Oxygen Species (ROS) is an integral feature of normal cellular function like mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. The release of oxygen free radicals has also been reported during the recovery phases from many pathological noxious stimuli to the cerebral tissues. Some of the neurodegenerative disorders include Alzheimer's disease, Huntington's disease, Parkinson's disease and Lateral sclerosis.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of neuromuscular disorders and neurodegenerative diseases.